Total Synthesis of the 7,3'-Linked Naphthylisoquinoline Alkaloid

a Reagents and conditions: (a) (EtO)2POCH2CO2Et, NaH, benzene, 0 °C to rt, ... Addition of 1 equiv of 2,4,6-collidine to the reaction, as reported by...
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Total Synthesis of the 7,3′-Linked Naphthylisoquinoline Alkaloid Ancistrocladidine Christopher J. Bungard‡ and Jonathan C. Morris*,† School of Chemistry and Physics, UniVersity of Adelaide, Adelaide, SA, Australia, and Department of Chemistry, UniVersity of Canterbury, Christchurch, New Zealand [email protected] ReceiVed June 4, 2006

The first total synthesis of ancistrocladidine, a rare 7,3′-linked naphthylisoquinoline alkaloid, has been completed, with the key feature of the synthesis being the formation of the extremely hindered biaryl linkage by ortho-arylation of a naphthol with an aryllead triacetate. Initial efforts were focused on the generation of a heteroaryl lead species, which would have allowed a convergent synthesis to be developed. However, it was not possible to generate such a lead species. A simpler aryl lead triacetate was prepared and reacted. The resulting biaryl aldehyde was elaborated in 10 steps to form a 1:1 mixture of ancistrocladidine and its atropisomer. Recrystallization of the mixture afforded ancistrocladidine, which was identical in all respects to the reported data.

Introduction The naphthylisoquinoline alkaloids are a large group of natural products whose only known sources are the Ancistrocladaceae and the closely related Dioncophyllaceae plant families.1 Extracts from the tropical Ancistrocladaceae and Dioncophyllaceae plant families have been used in traditional medicines for the treatment of malaria and dysentery.2 More recently, bioassay-directed isolation has led to the discovery of many structurally related compounds with biological activities such as antimalarial,3 antifeedant,4 molluscidal,5 insect growthretarding,6 and anti-HIV activity.7 Accordingly, structureactivity guided modifications, coupled with chemical syntheses of the natural products, has been a fruitful area of investigation for the development of more selective and active drugs.2b These structurally unique alkaloids are characterized by a naphthalene group, linked to either a dihydro- or tetrahydroisoquinoline moiety, as exemplified by the examples shown in Figure 1. As a result of the hindered nature of the biaryl bond, restricted rotation dictates that many of these compounds exist †

University of Adelaide. ‡ University of Canterbury.

(1) Bringmann, G.; Pokorny, F. In Alkaloids; Academic Press: New York, 1995; p 127. (2) (a) Bringmann, G.; Gramatzki, S.; Grimm, C.; Proksch, P. Phytochemistry 1992, 31, 3821-3825. (b) Bringmann, G.; Francois, G.; Ake Assi, L.; Schlauer, J. Chimia 1998, 52, 18-28.

FIGURE 1. Representative examples of naphthylisoquinoline alkaloids.

as thermally stable atropisomers.8 These natural products can be grouped according to the position of the biaryl bond linking the naphthalene and isoquinoline structural entities, with the 5,1′- and 7,1′-linkages being the most common. Ancistrocladidine (1a),9 ancistroheynine B (1b),10 ancistrotectorine (2a),11 and ancistrotanzanine C (2b)12 are some of the more unusual 10.1021/jo0611364 CCC: $33.50 © 2006 American Chemical Society

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Published on Web 08/19/2006

Total Synthesis of Ancistrocladidine

members of the naphthylisoquinoline family because of the presence of the highly hindered 7,3′-biaryl linkage. The challenging architecture of the naphthylisoquinoline alkaloids, combined with their interesting biological activity, has led to considerable interest from the synthetic community.13 The most successful strategy for the synthesis of these natural products is Bringmann’s lactone method,14 which provides ready access to the 5,1′- and 7,1′- linked members of the family in an atroposelective manner. Direct coupling of the appropriate naphthalene and isoquinoline moieties, under palladium catalysis, has also proved to be a rewarding approach.13g,15 However, little synthetic attention16 has been focused on 7,3′-linked systems such as that found in ancistrocladidine 1a as the highly hindered biaryl system presents a significant challenge to existing methods for the synthesis of the naphthylisoquinoline alkaloids. Although numerous palladium-catalyzed biaryl cross-couplings have been utilized in the synthesis17 of biaryls possessing one, two, or three ortho-substituents, a common trend in such reactions is a lowering in the yield of coupled product upon an increase in the steric bulk surrounding the resulting biaryl bond.18,19 For this reason there are only a few examples of couplings resulting in products that contain four ortho-substituents, although recent work by Buchwald has begun to rectify this situation.19 Perhaps more importantly, synthesis of an appropriate naphthalene precursor for the cross-coupling would not be a trivial process.20 For these reasons, an alternative biaryl

FIGURE 2. Retrosynthetic analysis.

coupling methodology for the formation of the 7-3′ linkage of ancistrocladidine was sought. The ortho-arylation of phenols with aryllead tricarboxylates is a reaction that is known to proceed on hindered substrates in an efficient manner.21 Furthermore, Yamamoto and co-workers have extended this ortho-arylation methodology even further to allow asymmetric coupling.22 This ortho-arylation chemistry has far-reaching implications with regards to a synthetic approach to a 7-3′ naphthylisoquinoline alkaloid (Figure 2). The possibility exists for direct functionalization of naphthol 3,23 which would circumvent the need for preparation of a difficult-to-access naphthalene precursor. In this paper, we present full details of this synthetic strategy and its application to the total synthesis of ancistrocladidine.24 Results and Discussion

(3) (a) Francois, G.; Bringmann, G.; Phillipson, J. D.; Assi, L. A.; Dochez, C.; Ru¨ebenacker, M.; Schneider, C.; We´ry, M.; Warhurst, D. C.; Kirby, G. C. Phytochemistry 1994, 35, 1461. (b) Bringmann, G.; Goetz, R.; Franc¸ ois, G. Tetrahedron 1996, 52, 13419. (c) Bringmann, G.; Koppler, D.; Wiesen, B.; Franc¸ ois, G.; Narayanan, A. S. S.; Almeida, M. R.; Schneider, H.; Zimmermann, U. Phytochemistry 1996, 43, 1405. (d) Bringmann, G.; Saeb, W.; Koppler, D.; Franc¸ ois, G. Tetrahedron 1996, 52, 13409. (e) Hallock, Y. F.; Caredellina, J. H., II; Scha¨ffer, M.; Stahl, M.; Bringmann, G.; Franc¸ ois, G.; Boyd, M. R. Tetrahedron 1997, 53, 8121. (g) Francois, G.; Timperman, G.; Eling, W.; Assi, L. A.; Holenz, J.; Bringmann, G. Antimicrob. Agents Chemother. 1997, 41, 2533-2539. (h) Bringmann, G.; Holenz, J.; Weirich, R.; Ru¨benacker, M.; Funke, C.; Boyd, M. R.; Gulakowski, R. J.; Franc¸ ois, G. Tetrahedron 1998, 54, 497. (i) Bringmann, G.; Saeb, W.; God, R.; Scha¨ffer, M.; Franc¸ ois, G.; Peters, K.; Peters, E.M.; Proksch, P.; Hostettmann, K.; Assi, L. A. Phytochemistry 1998, 49, 1667. (j) Bringmann, G.; Teltschik, F.; Michel, M.; Busemann, S.; Ru¨ckert, M.; Haller, R.; Ba¨r, S.; Robertson, S. A.; Kaminsky, R. Phytochemistry 1999, 52, 321. (k) Bringmann, G.; Saeb, W.; Wohlfarth, M.; Messer, K.; Brun, R. Tetrahedron 2000, 56, 5871. (l) Bringmann, G.; Saeb, W.; Kraus, J.; Brun, R.; Franc¸ ois, G. Tetrahedron 2000, 56, 3523. (m) Bringmann, G.; Gu¨nther, C.; Saeb, W.; Mies, J.; Wickramasinghe, A.; Mudogo, V.; Brun, R. J. Nat. Prod. 2000, 63, 1333. (n) Stiefl, N.; Bringmann, G.; Rummey, C.; Baumann, K. J. Comput.-Aided Mol. Design, 2003, 17, 347-365. (o) Bringmann, G.; Holzgrabe, U.; Hoerr, V.; Stich, A. Pharmazie 2003, 58, 343-346. (4) Bringmann, G.; Gramatzki, S.; Grimm, C.; Proksch, P. Phytochemistry 1992, 31, 3821. (5) Bringmann, G.; Holenz, J.; Assi, L. A.; Zhao, C. X.; Hostettmann, K. Planta Med. 1996, 62, 556. (6) (a) Bringmann, G.; Holenz, J.; Wiesen, B.; Nugroho, B. W.; Proksch, P. J. Nat. Prod. 1997, 60, 342. (b) Hallock, Y. F.; Cardellina, J. H., II; Scha¨ffer, M.; Bringmann, G.; Franc¸ ois, G.; Boyd, M. R. Bioorg. Med. Chem. Lett. 1998, 8, 1729. (7) (a) Manfredi, K. P.; Blunt, J. W.; Cardellina, J. H., II; McMahon, J. B.; Pannell, L. L.; Cragg, G. M.; Boyd, M. R. J. Med. Chem. 1991, 34, 3402. (b) Upender, V.; Pollart, D. J.; Liu, J.; Hobbs, P. D.; Olsen, C.; Chao, W.; Bowden, B.; Crase, J. L.; Thomas, D. W.; Pandey, A.; Lawson, J. A.; Dawson, M. I. J. Heterocycl. Chem. 1996, 33, 1371. (c) Zhang, H.; Zembower, D. E.; Chen, Z. Bioorg. Med. Chem. Lett. 1997, 7, 2687. (d) Hoye, T. R.; Chen, M.; Hoang, B.; Mi, L.; Priest, O. P. J. Org. Chem. 1999, 64, 7184. (e) Boyd, M. R.; Hallock, Y. F.; Cardellina, J. H., II; Manfredi, K. P.; Blunt, J. W.; McMahon, J. B.; Buckheit, R. W., Jr.; Bringmann, G.; Scha¨effer, M.; Cragg, G. M.; Thomas, D. W.; Jato, J. G. J. Med. Chem. 1994, 37, 1740.

Our initial efforts focused on the attractive possibility of preparing ancistrocladidine 1a in a convergent fashion by generating a lead reagent 4 whereby the entire heterocyclic moiety of ancistrocladidine is present (Figure 2). This would allow us to investigate Yamamoto’s methodology to control the atroposelectivity. Organolead compounds may be prepared by two routes, either by direct plumbation or by transmetalation.21c,f,25 The latter method is the more general route as it exhibits a greater tolerance (8) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994; p 1142. (9) (a) Govindachari, T. R.; Parthsarathy, P. C.; Desai, H. K. Indian J. Chem. 1973, 11, 1190. (b) Govindachari, T. R.; Parthasarathy, P. C.; Rajagopalan, T. G.; Desai, H. K.; Lee, E. J. Chem. Soc., Perkin Trans. 1 1975, 2134. (c) Kartha, G.; Parthsarathy, P. Indian J. Chem. 1983, 22B, 590. (d) Meksuriyen, D.; Ruangrungsi, N.; Tantivatana, P.; Cordell, G. A. Phytochemistry 1990, 29, 2750. (10) Bringmann, G.; Dreyer, M.; Michel, M.; Tayman, F. S. K.; Brun, R. Phytochemistry 2004, 65, 2903-2907. (11) (a) Ruangrungsi, N.; Wongpanich, V.; Tantivatana, P.; Cowe, H. J.; Cox, P. J.; Funayama, S.; Cordell, G. A. J. Nat. Prod. 1985, 48, 529. (b) Bringmann, G.; Gu¨nther, C.; Busemann, S.; Scha¨ffer, M.; Olowokudejo, J. D.; Alo, B. D. Phytochemistry 1998, 47, 37. (12) Bringmann, G.; Dreyer, M.; Faber, J. H.; Dalsgaard, P. W.; Strk, D.; Jaroszewski, J. W.; Ndangalasi, H.; Mbago, F.; Brun, R.; Christensen, S. B. J. Nat. Prod. 2004, 67, 743. (13) (a) Rao, A. V. R.; Gurjar, M. K.; Ramana, D. V.; Chheda, A. K. Heterocycles 1996, 43, 1-6. (b) Hobbs, P. D.; Upender, V.; Dawson, M. I. Synlett 1997, 965-967. (c) Chau, P.; Czuba, I. R.; Rizzacasa, M. A.; Bringmann, G.; Gulden, K.-P.; Scha¨ffer, M. J. Org. Chem. 1996, 61, 71017105. (d) Rizzacasa, M. A. In Studies in Natural Product Synthesis, Structure and Chemistry, Part F; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1998; Vol. 20, pp 407-455 and references therein. (e) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525-558 and references therein. (f) Lipshutz, B. H.; Keith, J. M. Angew. Chem., Int. Ed. 1999, 38, 3530-3533. (g) Hoye, T. R.; Chen, M.; Hoang, B.; Mi, L.; Priest, O. P. J. Org. Chem. 1999, 64, 7184-7201. (h) Kamikawa, K.; Watanabe, T.; Daimon, A.; Uemura, M. Tetrahedron 2000, 56, 2325-2337. (i) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615-624 and references therein.

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Bungard and Morris SCHEME 1 a

a Reagents and conditions: (a) (EtO) POCH CO Et, NaH, benzene, 0 °C to rt, 100%; (b) DIBAL, CH Cl , 0 °C, 80%; (c) VO(acac) , t-BuOOH, CH Cl , 2 2 2 2 2 2 2 2 rt, 91%; (d) TsCl, NEt3, DMAP, CH2Cl2, 0 °C, 95%; (e) DIBAL, CH2Cl2, -20 °C to rt, 94%. (f) phthalimide, PPh3, DEAD, THF, 0 °C to rt, 81%; (g) MeNH2, H2O/EtOH, reflux; (h) HCl (g), ether, 0 °C, 91% for 2 steps; (i) CH3COCl, NEt3, CH2Cl2, 0 °C to rt, 96%; (j) POCl3, 2,4,6-collidine, CH3CN, reflux, 89%. (k) t-BuLi, THF, -95 °C, ClSnBu3, -95 °C to rt, 83%. (l) Pb(OAc)4, cat. Hg(OAc)2, CHCl3.

of functionality. This metal-metal exchange route is normally achieved using either a tin or boron species in the presence of catalytic amounts of mercuric(II) salts.25c,d Tin-lead exchange has proven to be the method of choice in many cases because (14) (a) Bringmann, G.; Breuning, M.; Pfeifer, R.-M.; Schenk, W. A.; Kamikawa, K.; Uemura, M. J. Organomet. Chem. 2002, 661, 31-47. (b) Bringmann, G.; Tasler, S.; Pfeifer, R.-M.; Breuning, M. J. Organomet. Chem. 2002, 661, 49-65 and references therein. (c) Bringmann, G.; Pfeifer, R.-M.; Schreiber, P.; Hartner, K.; Schraut, M.; Breuning M. Tetrahedron 2004, 60, 4349-4360 and references therein. (15) (a) Bringmann, G.; Hamm, A.; Schraut, M. Org. Lett. 2003, 5, 2805-2808. (b) Bringmann, G.; Guenther, C. Synlett 1999, 216-218. (c) Watanabe, T.; Tanaka, Y.; Shoda, R.; Sakamoto, R.; Kamikawa, K.; Uemura, M. J. Org. Chem. 2004, 69, 4152-4158. (16) Comber, M. F.; Morris, J. C.; Sargent, M. V. Aust. J. Chem. 1998, 51, 19-22. (17) (a) Stanforth, S. P. Tetrahedron 1998, 54, 263-303. (b) MetalCatalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998. (c) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384-5427. (18) (a) Johnson, M. G.; Foglesong, R. J. Tetrahedron Lett. 1997, 38, 7001-7002. (b) Saa´, J. M.; Martorell, G. J. Org. Chem. 1993, 58, 19631966. (19) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685-4696. (20) For example, 2-bromo-3-methyl-8-methoxy-1-naphthol has been prepared by Nishiyama and Kameoka via an eight-step sequence, in 7.5% overall yield, from (3-methoxyphenyl)-2-propanone. Although useful, the sequence required many purification steps and included a poor-yielding bromination step (23%). Nishiyama, T.; Kameoka, H. Chem. Express 1991, 6, 109. (21) The groups of Pinhey and Barton have shown that this is an efficient method for the generation of extremely hindered biaryl linkages: (a) Bell, H. C.; Pinhey, J. T.; Sternhell, S. Aust. J. Chem. 1979, 32, 1551-1560. (b) Morgan, J.; Hambley, T. W.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1996, 2173-2177. (c) Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353-1382. (d) Barton, D. H. R.; Donnelly, D. M. X.; Guiry, P. J.; Finet, J.-P. J. Chem. Soc., Perkin Trans. 1 1994, 2921-2926. (e) Pinhey, J. T. In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 11, p 461. (f) For an excellent overview of aryllead chemistry, see: Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5683-5705. (22) (a) Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943 and references therein. (b) Kano, T.; Ohyabu, Y.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 53655373. (23) (a) Watanabe, M.; Hisamatsu, S.; Hotokezaka, H.; Furukawa, S. Chem. Pharm. Bull. 1986, 34, 2810-2820. (b) Bungard, C. J.; Morris, J. C. J. Org. Chem. 2002, 67, 2361-2364. (24) A preliminary communication of this work has been published: Bungard, C. J.; Morris, J. C. Org. Lett. 2002, 4, 631-633.

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of the ease of purification of the resulting organolead compounds. With this in mind, synthesis of stannane 5 was our first concern (Figure 2). To generate this compound, we required 7-iododihydroisoquinoline 6. With the Bischler-Napieralski reaction being the standard method26 for preparing dihydroisoquinolines, access to amphetamine 7 was necessary. Although there are several excellent syntheses26,27 of such compounds en route to dihydroisoquinolines, the majority are not compatible with the iodo moiety due to the strong reducing agents utilized. Investigations into the Preparation of Heterocyclic Lead Triacetates. Rao and co-workers13a have reported a synthesis that utilizes mild conditions, which we felt would be amenable to the preparation of the iodide 6. Furthermore, it would allow for the preparation of chiral material. However, our initial efforts were focused on the preparation of 7 in a racemic form. Starting from aldehyde 8,29 the required allylic alcohol 9 was readily prepared in 80% yield by first forming the R,β-unsaturated ester 10 by Horner-Wadsworth-Emmons reaction and then reduction with DIBAL-H (Scheme 1). Treatment of allylic alcohol 9 with catalytic vanadyl acetylacetonate and t-BuOOH in dichloromethane gave epoxide 11 in 91% yield after chromatography.28 Conversion of this epoxide to the secondary alcohol 12 was achieved utilizing a method reported by Chong.30 Tosylate 13 was readily prepared from epoxyalcohol 11 in 95% yield. (25) (a) Bell, H. C.; Kalman, J. R.; Pinhey, J. T.; Sternhell, S. Aust. J. Chem. 1979, 32, 1521. (b) Kozyrod, R. P.; Pinhey, J. T. Tetrahedron Lett. 1983, 24, 1301-1302. (c) Kozyrod, R. P.; Morgan, J.; Pinhey, J. 1985, 38, 1147. (d) Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1990, 715. (26) (a) Rizzacasa, M. A.; Sargent, M. V.; Skelton, B. W.; White, A. H. Aust. J. Chem. 1990, 43, 79-86. (b) Bringmann, G.; Weirich, R.; Reuscher, H.; Jansen, J. R.; Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877-888. (27) (a) Bringmann, G.; Jansen, J. R.; Rink, H.-P. Angew. Chem., Int. Ed. Engl. 1986, 25, 913. (b) Hoye, T. R.; Chen, M. Tetrahedron Lett. 1996, 37, 3099. (c) Lipshutz, B. H.; Keith, J. M. Angew. Chem., Int. Ed. 1999, 38, 3530. (d) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W. Org. Lett. 2000, 2, 3901-3903. (28) The aldehyde 8 is readily available from 3,5-dihydroxybenzoic acid as described in (a) Gray, J. S.; Martin, G. C. J.; Rigby, W. J. Chem. Soc. C 1967, 2580-2587. (b) Kompis, I.; Wick, A. HelV. Chim. Acta 1977, 8, 3025-3034. (29) Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.; Michaelson, R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974, 96, 5254. (30) Chong, J. M. Tetrahedron Lett. 1992, 33, 33-36.

Total Synthesis of Ancistrocladidine SCHEME 2 a

Subsequent reduction with DIBAL-H in dichloromethane gave alcohol 12 in 94% yield after chromatography. Reaction of alcohol 12 with triphenylphosphine, phthalimide, and diethyl azodicarboxylate in THF gave imide 14 in 81% yield. Deprotection of the phthalmide was readily accomplished by refluxing 14 in an ethanolic solution of aqueous methylamine to give the amine 7, which was isolated in 91% yield as its hydrochloride salt 15. Hydrochloride 15 was smoothly acetylated using acetyl chloride and triethylamine in dichloromethane to give acetamide 16 in 96% yield. However, the ensuing Bischler-Napieralski cyclization was problematic. Exposure of 16 to the standard cyclization conditions of phosphorus oxychloride in acetonitrile, at reflux, resulted in varying degrees of deiodination. Addition of 1 equiv of 2,4,6-collidine to the reaction, as reported by Lipshutz and Keith,26c afforded the desired dihydroisoquinoline 6 in 89% yield. The stannane 5 was readily prepared in 83% yield by treatment of iodide 6 with t-BuLi at -95 °C in THF, followed by addition of tributyltin chloride. The standard preparation of aryl lead triacetates involves stirring the stannane with freshly purified Pb(OAc)4 in the presence of a catalytic amount of Hg(OAc)2. Unfortunately, exposure of stannane 5 to these conditions resulted in a complex mixture, from which only starting material could be isolated. The reaction was repeated at room temperature, and it was noted that upon addition of 5 to a solution of Pb(OAc)4, red coloration and precipitation of material resulted. The precipitated material appeared to dissolve in water, but no useful information could be gathered from the resulting 1H NMR spectrum run in D O. On the assumption that the Pb2 (OAc)4 and/or Hg(OAc)2 were reacting with the imine group, it was decided to investigate whether the tetrahydroisoquinoline may be a more suitable compound for the generation of an aryl lead triacetate. Tetrahydroisoquinoline 17 was selected as it is the same as the tetrahydroisoquinoline moiety present in the other 7-3′-linked naphthylisoquinoline alkaloid, ancistrotectorine 2a, and thus could be utilized in a total synthesis. It is well documented that reduction of 3,4-dihydroisoquinolines with sodium borohydride in methanol gives cis-configured tetrahydroisoquinolines.26b These can be converted into their N-methyl derivatives by preparation of the carbamate, followed by lithium aluminum hydride reduction.13c However, the iodide functionality is not compatible with such a reducing agent, and therefore an alternative method was sought. Rizzacasa and Sargent have shown that upon N-methylation of dihydroisoquinoline 18, reduction of the resulting tetrahydroisoquinolinium salt, with sodium borohydride, affords a 2:1 mixture of tetrahydroisoquinolines in favor of the trans-isomer.26a As ancistrotectorine contains a cis arrangement of the methyl groups, an alternative reducing agent was required. There was evidence to suggest that reduction of isoquinolinium salts with the bulkier diisobutylaluminum hydride should give the desired cis-selectivity.31 Accordingly, N-methyldihydroisoquinoline 19 was readily prepared by treating a solution of dihydroisoquinoline 6 in acetone with iodomethane (Scheme 2). The so-obtained salt was reduced with DIBAL-H in dichloromethane at -78 °C to afford a 9:1 ratio of diastereoisomers, which after chromatography afforded the cis-diastereoisomer 20 in 85% yield. The relative configuration was confirmed by deiodination, using t-BuLi then H2O, which gave the tetrahydroisoquinoline cis-21, which had previously been prepared by Sargent and

Rizzacasa.26a The observed stereoselectivity for the reduction of the isoquinoline could be explained in terms of the bulky reducing agent delivering a hydride from the opposite face with respect to the methyl group at 3-position. Stannane 22 was prepared in 56% yield from iodide 20 by halogen/metal exchange, followed by addition of tributyltin chloride. Stirring a solution of the stannane 22, Pb(OAc)4, and Hg(OAc)2 at room temperature gave only recovered starting material and a small amount of demetalated material 21. Repeating the reaction, but at 40 °C resulted in complete demetalation to form 21. Barton and co-workers have observed that aryllead reagents can be demetalated by arylamines via an oxidation mechanism.32 Two potential solutions to this problem were considered at this stage. First, in situ trapping of the aryllead species 17 with naphthol 3, which may be a faster process than the proposed oxidation, or second, an electronwithdrawing group could be attached to the nitrogen atom of the tetrahydroisoquinoline, thus decreasing the basicity of the lone pair of electrons and slowing the undesired nucleophilic addition to lead. Unfortunately, conducting the plumbation reaction in the presence of naphthol 3 and pyridine resulted in a complex mixture from which only starting materials and demetalated species could be isolated. No trace of a orthoarylated naphthol was found. Carbamate 23 was chosen as the precursor to aryllead species 24 as the carbamate group would provide significant withdrawal of electron density from the nitrogen and still be readily converted into an N-methyl derivative as is required for the synthesis of ancistrotectorine 2a (Scheme 3). Thus, stannane 5 was readily reduced with sodium borohydride in methanol to give amine 25 in 96% yield. Carbamate 23 was prepared in 77% yield by reacting amine 25 with methyl chloroformate in dichloromethane, in the presence of triethylamine. Interestingly the aliphatic CH signals were significantly broadened in the 1H

(31) Martens, J. In Methods of Organic Chemistry, workbench ed. E21; Georg Thieme Verlag: Stuttgart, 1996; Vol. 7, p 4220.

(32) Barton, D. H.; Donnelly, D. M. X.; Finet, J.-P.; Guiry, P. J. J. Chem. Soc., Perkin Trans. 1 1991, 2095.

a Reagents and conditions: (a) MeI, acetone, rt; (b) DIBAL, CH Cl , 2 2 -78 °C to rt, 85% for 2 steps; (c) t-BuLi/H2O, THF, -78 °C; (d) t-BuLi, THF, -95 °C, ClSnBu3, - 95 °C to rt, 83%.

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Bungard and Morris SCHEME 3 a

SCHEME 4 a

a Reagents and conditions: (a) NaBH , MeOH, rt, 96%; (b) ClCO Me, 4 2 NEt3, CH2Cl2, rt, 77%; (c) Pb(OAc)4, cat. Hg(OAc)2, CHCl3

NMR spectrum of 23. This may arise from a slowing of the rate of pyramidal inversion at nitrogen by the electronwithdrawing carbamate group Unfortunately, stirring of 23 with Pb(OAc)4 and Hg(OAc)2 in chloroform at room temperature gave only recovered starting material and a small amount of demetalated material. Conducting the reaction at 40 °C resulted in an increase in the amount of demetalated material. The inability of stannanes 4, 22, and 23 to form an aryllead species could be due to a number of factors. The presence of a nitrogen atom containing a basic lone pair of electrons could be detrimental, as it has been shown that nitrogen-containing species such as pyridine interact strongly with aryllead triacetates in solution. A possible steric argument can also be considered when discussing aryllead tricarboxylate 4. A steric clash between the C8 methoxy group and the C1 methyl group in 4 could cause a subtle compression of the steric environment between the methoxy groups resulting in an inability to form a lead-species. It is possible to remove the issues associated with the nitrogen atom and those associated with steric crowding by investigating the synthesis of aryllead tricarboxylate 25. Preparation of an Aryl Lead Triacetate. Iodide 26 was prepared by acetalization of iodobenzaldehyde 828 with ethylene glycol (99%) (Scheme 4). Conversion to the stannane 27 was achieved by halogen-lithium exchange of iodide 26 with t-BuLi and subsequent quenching with Bu3SnCl. To our delight, stirring the stannane 27 with freshly purified Pb(OAc)4 in the presence of a catalytic amount of Hg(OAc)2 provided aryllead triacetate 25 in 93% yield. Formation of the key biaryl linkage using the Pinhey-Barton methodology was readily achieved by reaction of the lead species 25 with naphthol 3 in the presence of pyridine and CH2Cl2 at room temperature. Hydrolysis of the crude reaction mixture with 3% v/v aqueous H2SO4 in THF gave the desired biaryl aldehyde 28, in 67% yield from 3. Completion of the Synthesis of Ancistrocladidine. With the successful establishment of the hindered biaryl linkage, aldehyde 28 was then elaborated to the chiral amine 29, with the Katsuki-Sharpless asymmetric epoxidation being used to set the stereochemistry at C3 (Scheme 5).13a The required allylic alcohol 30 was prepared in three steps from biaryl aldehyde 28 in 71% overall yield: (i) protection of the naphthol as its MOM ether, (ii) elaboration of the aldehyde to the R,β-unsaturated ester by Horner-Wadsworth-Emmons reaction, and (iii) reduction with DIBAL-H. 7358 J. Org. Chem., Vol. 71, No. 19, 2006

a Reagents and conditions: (a) 1,2-ethanediol, cat. TsOH, benzene, Dean-Stark, 99%. (b) t-BuLi, Bu3SnCl, THF, -95 °C - rt, 85%; (c) Pb(OAc)4, cat. Hg(OAc)2, CH2Cl2, rt, 24 h, 93%; (d) 3, pyridine, CH2Cl2, 24 h, rt; (e) 3% v/v aqueous H2SO4, THF, 1 h, rt, 67% yield from 3.

Using the standard Sharpless conditions,33 the epoxide 31 was obtained in 80% yield and 90% de.34 This reaction generates diastereomers with respect to the biaryl linkage, but they were not observable. The epoxide was recrystallized from toluene/ petroleum ether to provide material with >95% de (63% yield). Tosylation of 31 gave the tosylate 32 in 83% yield. Concomitant cleavage of the tosylate and ring opening of the epoxide to afford alcohol 33, in 94% yield, was achieved by reaction of tosylate 32 with LiAlH4 in Et2O. Transformation of the alcohol 33 into the amine 29 was achieved, in 81% overall yield, by reaction of 33 with phthalimide as described earlier, followed by hydrolysis of the phthalimide group with aqueous ethanolic methylamine. Acetylation of the resulting amine 29 with CH3COCl gave the acetamide 34 in 97% yield. Bischler-Napieralski cyclization was readily achieved by reaction of 34 with POCl3 in the presence of 1.1 equiv of 2,4,6-collidine. During the course of this reaction, the MOM protecting group was cleaved in situ, and thus, ancistrocladidine 1a was isolated, along with the atropisomer 35, in a 1:1 ratio, in 74% overall yield. Separation of the atropisomers was readily achieved by recrystallization as the non-natural atropisomer 35 proved to be noncrystalline. While comparison with an authentic sample of ancistrocladidine is not possible as the natural product is no longer available, synthetic ancistrocladidine matches all the reported data for the natural product.9 In summary, the first total synthesis of a 7,3′-linked naphthylisoquinoline alkaloid has been completed. The key feature of our synthesis is the formation of the extremely hindered biaryl linkage by ortho-arylation of a naphthol with an aryllead triacetate. Future work will involve the application of this strategy to other members of the naphthylisoquinoline alkaloid family, with the ultimate goal being the generation of such compounds as single atropoisomers. (33) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. (34) The diasteromeric excess of this reaction was determined by the method described in Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543-2549. Details are provided in Supporting Information.

Total Synthesis of Ancistrocladidine SCHEME 5 a

a Reagents and conditions: (a) MOM-Cl, NaH, THF, rt, 81%; (b) NaH, (EtO) POCH CO Et, C H , 0 °C - rt, 99%; (c) DIBAL-H, toluene, -78 °C, 15 2 2 2 6 6 min., 89%; (d) 5 mol % Ti(OiPr)4, 6 mol % D-diisopropyltartrate, TBHP, CH2Cl2, -20 °C, 5 h, 80%, 90% ee; (e) TsCl, NEt3, DMAP, CH2Cl2, 1 h, 0 °C, 83%; (f) LiAlH4, Et2O, 0 °C, 2 h, 94%; (g) phthalimide, DEAD, PPh3, THF, rt, 16 h, 82%; (h) 40% aq MeNH2, EtOH, reflux, 1 h, 99%; (i) CH3COCl, NEt3, CH2Cl2, 0 °C - rt, 97%; (j) POCl3, 2,4,6-collidine, CH3CN, reflux, 4 h, 74% (1:1 mixture of 1a and 35).

Experimental Section35 (E)-3-(4-Iodo-3,5-dimethoxyphenyl)-acrylic Acid Ethyl Ester (10). Triethyl phosphonoacetate (1.58 mL, 7.94 mmol) was added to a suspension of prewashed NaH (208 mg, 8.67 mmol) in dry benzene (20 mL) at 0 °C. The reaction was stirred for 15 min, and then a solution of the aldehyde 828 (2.11 g, 7.22 mmol) in dry benzene (30 mL) was slowly added. The reaction was stirred for 1 h at 0 °C, then 30 min at room temperature, following which H2O was added. The aqueous layer was extracted with EtOAc (×4) and the combined organic extracts were washed with H2O (×2). Removal of the solvent under reduced pressure gave the title compound as a white solid (2.62 g, 100%). Mp: 135-136 °C. 1H NMR (500 MHz, CDCl3): δ 1.34 (t, J ) 7.3 Hz, 3H), 3.92 (s, 6H), 4.27 (q, J ) 7.3 Hz, 2H), 6.47 (d, J ) 16 Hz, 1H), 6.63 (s, 2H), 7.62 (d, J ) 16 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.2, 56.4, 60.5, 80.2, 103.2, 118.9, 136.1, 143.7, 159.5, 166.5. IR (KBr): 1703 cm-1. HRMS: calcd for C13H15IO4 (M+) 362.0014, found 362.0015. (E)-3-(4-Iodo-3,5-dimethoxyphenyl)prop-2-en-1-ol (9). Neat DIBAL-H (2.88 mL, 16.2 mmol) was added dropwise to a solution of the ester 10 (2.34 g, 6.47 mmol) in dry CH2Cl2 (40 mL) at 0 °C. The reaction was stirred at 0 °C for 1 h and quenched by dropwise addition of H2O until coagulation occurred. The suspension was diluted with 1 M aqueous HCl solution and extracted with EtOAc (×4). Removal of the solvent under reduced pressure and purification of the residue by flash chromatography, eluting with 70% EtOAc/petroleum ether, gave the title compound as a white solid (1.65 g, 80%). Mp: 122-123 °C. 1H NMR (500 MHz, CDCl3): δ 3.89 (s, 6H), 4.34 (d, J ) 4.9 Hz, 2H), 6.41 (dt, J ) 16, 5.4 Hz, 1H), 6.53 (s, 2H), 6.58 (dd, J ) 16, 1.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 56.4, 63.1, 76.5, 102.1, 129.5, 130.1, 138.6, 159.2. IR (film): 3209 cm-1. HRMS: calcd for C11H13IO3 (M+) 319.9908, found 319.9910. (2S*,3R*)- (3-[4-Iodo-3,5-dimethoxyphenyl]oxiranyl)-methanol ((11). Anhydrous TBHP solution (6.1 M, 67.2 mmol) in CH2Cl2 (0.52 mL) was added to a solution of the allylic alcohol 9 (500 (35) General procedures are detailed in Supporting Information.

mg, 1.6 mmol) and VO(acac)2 (8 mg, 3.1 µmol) in dry CH2Cl2 (5 mL). The reaction was stirred for 1 h at room temperature, diluted with CH2Cl2, and filtered through a plug of Celite. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with 70% EtOAc/petroleum ether, to give the title compound as a white solid (480 mg, 91%). Mp: 99-100 °C. 1H NMR (500 MHz, CDCl3): δ 1.82 (d, J ) 7.8 Hz, 1H), 3.17 (m, 1H), 3.82 (m, 1H), 3.88 (s, 6H), 3.94 (d, J ) 2.0 Hz, 1H), 4.06 (m, 1H), 6.44 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 55.3, 56.5, 60.9, 62.6, 76.8, 101.1, 139.3, 159.5. IR (KBr): 3412 cm-1. HRMS: calcd for C11H13IO4 (M+) 335.9857, found 335.9859. (2S*,3R*)-Toluene-4-sulfonic Acid 3-(4-Iodo-3,5-dimethoxyphenyl)oxiranyl-methyl Ester ((13). Dry NEt3 (1.69 mL, 12.2 mmol) was added to a solution of the alcohol 11 (0.816 g, 2.43 mmol) and DMAP (0.297 g, 2.43 mmol) in dry CH2Cl2 (25 mL) at 0 °C. A solution of TsCl (0.510 g, 2.67 mmol) in dry CH2Cl2 (3 mL) was slowly added. The reaction was stirred at 0 °C for 1 h, diluted with CH2Cl2, and washed in turn with 1 M aqueous HCl solution and saturated aqueous NaHCO3 solution. Removal of the solvent under reduced pressure gave the title compound as a fluffy white solid (1.13 g, 95%). Mp: 48-49 °C. 1H NMR (500 MHz, CDCl3): δ 2.45 (s, 3H), 3.19 (m, 1H), 3.80 (d, J ) 2.0 Hz, 1H), 3.86 (s, 6H), 4.15 (dd, J ) 12, 4.2 Hz, 1H), 4.33 (dd, J ) 12, 3.4 Hz, 1H), 6.37 (s, 2H), 7.35 (d, J ) 8.3 Hz, 2H), 7.81 (d, J ) 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 21.5, 56.0, 56.4, 58.5, 69.0, 77.2, 101.0, 127.8, 129.8, 132.3, 138.1, 145.1, 159.4. HRMS: calcd for C18H19IO6S (M+) 489.9946, found 489.9947. 1-(4-Iodo-3,5-dimethoxyphenyl)-propan-2-ol ((12). Neat DIBAL (1.23 mL, 6.91 mmol) was added dropwise to a solution of the tosylate 13 (1.13 g, 2.30 mmol) in dry CH2Cl2 (35 mL) at 15 °C. The resulting solution was stirred for 2 h at 15 °C and then allowed to warm to room temperature overnight. The reaction was quenched by dropwise addition of H2O, till coagulation occurred. The suspension was diluted with 1 M aqueous HCl solution and then extracted with EtOAc (×4). The combined organic extracts were washed with saturated aqueous NaHCO3 solution. Removal of the solvent under reduced pressure and purification by flash chromatography, eluting with 60% EtOAc/petroleum ether, gave the title J. Org. Chem, Vol. 71, No. 19, 2006 7359

Bungard and Morris compound as a colorless viscous oil (693 mg, 94%). 1H NMR (500 MHz, CDCl3): δ 1.25 (d, J ) 6.4 Hz, 3H), 2.65 (dd, J ) 13, 8.3 Hz, 1H), 2.76 (dd, J ) 14, 4.4 Hz, 1H), 3.87 (s, 3H), 4.01 (m, 1H), 6.36 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 22.7, 45.8, 56.3, 68.4, 74.1, 105.1, 140.9, 159.0. IR (film): 3385, 3547 cm-1. HRMS: calcd for C11H15IO3 (M+) 322.0066, found 322.0065. 2-(2-(4-Iodo-3,5-dimethoxyphenyl)-1-methylethyl)isoindole1,3-dione ((14). DEAD (0.422 mL, 0.570 mmol) was added to a solution of the alcohol 12 (693 mg, 2.15 mmol), PPh3 (0.705 g, 2.69 mmol), and phthalimide (0.396 g, 2.69 mmol) in dry THF (20 mL) at 0 °C. The reaction was protected from light and allowed to warm to room temperature overnight. Saturated aqueous NaHCO3 solution was added, and the product was extracted with EtOAc (×4). The combined organic extracts were washed with saturated aqueous NaHCO3 solution. The solvent was removed under reduced pressure, and purification by flash chromatography, eluting with 25% EtOAc/petroleum ether, gave the title compound as a white solid (786 mg, 81%). Mp: 124-125 °C. 1H NMR (500 MHz, CDCl3): δ 1.55 (d, J ) 6.8 Hz, 3H), 3.06 (dd, J ) 14, 6.4 Hz, 1H), 3.37 (dd, J ) 10, 14 Hz, 1H), 3.76 (s, 6H), 4.70 (m, 1H), 6.32 (s, 2H), 7.67 (m, 2H), 7.75 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 18.4, 39.8, 47.8, 56.3, 74.9, 104.7, 122.9, 131.6, 133.8, 140.7, 159.1, 168.2. IR (KBr): 1705 cm-1. HRMS: calcd for C19H18INO4 (M+) 451.0279, found 451.0281. 2-(4-Iodo-3,5-dimethoxyphenyl)-1-methylethylammonium Chloride ((15). 40% Aqueous MeNH2 solution (33 mL) was added to a solution of the imide 14 (0.786 g, 1.74 mmol) in absolute EtOH (50 mL). The reaction was heated at reflux for 1 h, and then most of the EtOH was removed under reduced pressure. H2O was added, the product was extracted with Et2O (×4), and the combined organic extracts were concentrated to a volume of ca. 25 mL. The resulting solution was cooled to 0 °C and purged with gaseous HCl for 15 min. The resulting white precipitate was collected by filtration and dried under reduced pressure to give the title compound as a white solid (566 mg, 91%). Mp: 230-231 °C dec. 1H NMR (500 MHz, CD3OD): δ 1.30 (d, J ) 6.4 Hz, 3H), 2.86 (dd, J ) 14, 7.8 Hz, 1H), 2.95 (dd, J ) 14, 6.8 Hz, 1H), 3.59 (m, 1H), 3.87 (s, 6H), 6.52 (s, 2H). 13C NMR (75 MHz, CD3OD): δ 18.9, 42.2, 50.4, 57.4, 76.8, 106.6, 140.2, 161.5. IR (KBr): 1415, 3431 cm-1. HRMS: electrospray calcd for C11H17INO2 (M+) 322.0304, found 322.0319. N-(2-(4-Iodo-3,5-dimethoxyphenyl)-1-methylethyl)acetamide ((16). Dry NEt3 (0.722 mL, 5.18 mmol) was added to a suspension of the hydrochloride 15 (842 mg, 2.35 mmol) in dry CH2Cl2 (20 mL) at 0 °C. Freshly distilled acetyl chloride (194 µL, 2.71 mmol) was slowly added, and the reaction was warmed to room temperature overnight. The resulting solution was diluted with CH2Cl2 and washed with 1 M aqueous HCl solution (×3). Removal of the solvent under reduced pressure gave the title compound as a white solid (817 mg, 96%). Mp: 142-143 °C. 1H NMR (500 MHz, CDCl3): δ 1.12 (d, J ) 6.4 Hz, 3H), 1.94 (s, 3H), 2.65 (dd, J ) 14, 7.8 Hz, 1H), 2.87 (dd, J ) 14, 5.4 Hz, 1H), 3.86 (s, 6H), 4.26 (m, 1H), 5.33 (d, J ) 7.3 Hz, 1H), 6.33 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 19.8, 23.2, 42.5, 45.8, 56.3, 74.8, 105.1, 140.5, 159.0, 169.2. IR (KBr): 1570, 1630, 3076, 3242 cm-1. HRMS: calcd for C13H19INO3 (M+) 364.0410, found 364.0411. 7-Iodo-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline ((6). 2,4,6-Collidine (173 µL, 1.30 mmol) was added to a solution of the amide 16 (429 mg, 1.18 mmol) in dry CH3CN (6 mL). Freshly distilled POCl3 (121 µL, 1.30 mmol) was added, and the reaction was heated at reflux for 3 h. The resulting solution was poured into saturated aqueous NaHCO3 solution and extracted with EtOAc (×4). The solvent was removed under reduced pressure, and purification by flash chromatography on alumina, eluting with 30% EtOAc/petroleum ether, gave the title compound as a light tan solid (364 mg, 89%). Mp: 91-92 °C. 1H NMR (500 MHz, CDCl3): δ 1.37 (d, J ) 6.8 Hz, 3H), 2.30 (dd, J ) 16, 13 Hz, 1H), 2.45 (d, J ) 2.0 Hz, 3H), 2.61 (dd, J ) 16, 4.4 Hz, 1H), 3.33 (m, 1H), 3.73 (s, 3H), 3.90 (s, 3H), 6.47 (s, 1H). 13C NMR (75 MHz, 7360 J. Org. Chem., Vol. 71, No. 19, 2006

CDCl3): δ 21.6, 25.7, 34.6, 51.3, 56.5, 61.9, 82.4, 105.9, 117.3, 142.5, 159.0, 160.2, 161.7. HRMS: calcd for C13H16INO2 (M+) 345.0225, found 345.0226. 6,8-Dimethoxy-1,3-dimethyl-7-tributylstannanyl-3,4-dihydroisoquinoline ((5). A solution of t-BuLi in pentane (1.5 M, 0.707 mL, 1.06 mmol) was added dropwise to a solution of the iodide 6 (154 mg, 0.424 mmol) in dry THF (4 mL) at -95 °C. The reaction was stirred at -95 °C for 15 min, then ClSnBu3 (0.288 mL, 1.06 mmol) was slowly added, and the reaction allowed to warm to room temperature overnight. The resulting solution was poured into saturated aqueous NaHCO3 solution and extracted with EtOAc (×4). Removal of the solvent under reduced pressure and purification by flash chromatography on alumina, eluting with 15% EtOAc/ petroleum ether, gave the title compound as a colorless oil (179 mg, 83%). 1H NMR (500 MHz, CDCl3): δ 0.88 (m, 9H), 1.07 (m, 6H), 1.32 (m, 6H), 1.39 (d, J ) 6.8 Hz, 3H), 1.51 (m, 6H), 2.33 (dd, J ) 16, 14 Hz, 1H), 2.43 (d, J ) 2.0 Hz, 3H), 2.60 (dd, J ) 16, 4.4 Hz, 1H), 3.32 (m, 1H), 3.56 (s, 3H), 3.77 (s, 3H), 6.44 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 11.2, 13.6, 22.0, 25.5, 27.3, 29.1, 35.2, 51.6, 55.2, 63.1, 104.5, 117.0, 121.0, 144.0, 163.2, 164.9, 165.9. HRMS: calcd for C25H43NSnO2 (M+ - Bu) 452.1612, found 452.1612. (1R*,3S*)-7-Iodo-6,8-dimethoxy-1,2,3-trimethyl-1,2,3,4-tetrahydroisoquinoline ((20). Iodomethane (212 µL, 3.40 mmol) was added to a solution of the dihydroisoquinoline 6 (235 mg, 0.680 mmol) in dry acetone (7 mL), followed by stirring at room temperature for 48 h. The solvent was removed under reduced pressure and the residue dissolved in dry CH2Cl2 and cooled to -78 °C. Neat DIBAL (145 µL, 0.816 mmol) was added, and the reaction allowed to warm to room temperature overnight. The reaction was quenched by dropwise addition of H2O till coagulation occurred. The suspension was diluted with 1 M aqueous HCl solution, stirred for 5 min, and then neutralized with 1 M aqueous NaOH solution. The product was extracted with CH2Cl2 (×4), and the solvent was removed under reduced pressure. Purification by flash chromatography on alumina, eluting with 15% EtOAc/ petroleum ether, gave the title compound as a pale yellow solid (209 mg, 85%). Mp: 79-80 °C. 1H NMR (500 MHz, CDCl3): δ 1.23 (d, J ) 6.4 Hz, 3H), 1.40 (d, J ) 6.8 Hz, 3H), 2.44 (m, 1H), 2.45 (s, 3H), 2.59 (dd, J ) 16, 2.9 Hz, 1H), 2.67 (dd, J ) 10, 16 Hz, 1H), 3.68 (q, J ) 6.4 Hz, 1H), 3.79 (s, 3H), 3.85 (s, 3H), 6.38 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 21.3, 23.2, 38.3, 41.4, 55.0, 56.4, 57.5, 60.5, 81.2, 106.6, 126.7, 138.5, 157.0, 157.6. HRMS: calcd for C14H19INO2 (M+) 360.0459, found 360.0461. (1R*,3S*)-6,8-Dimethoxy-1,2,3-trimethyl-7-tributylstannanyl1,2,3,4-tetrahydroisoquinoline ((22). A solution of t-BuLi in pentane (1.5 M, 0.489 mL, 0.734 mmol) was added dropwise to a solution of the iodide 20 (0.106 g, 0.293 mmol) in dry THF (3 mL) at -95 °C. The reaction was stirred at -95 °C for 15 min then ClSnBu3 (0.200 mL, 0.734 mmol) was slowly added, and the reaction was allowed to warm to room temperature overnight. The resulting solution was poured into saturated aqueous NaHCO3 solution and extracted with EtOAc (×4). The solvent was removed under reduced pressure and purification by flash chromatography on alumina, eluting with 5% EtOAc/petroleum ether, gave the title compound as a colorless oil (87 mg, 56%). 1H NMR (500 MHz, CDCl3): δ 0.88 (m, 9H), 1.07 (m, 6H), 1.23 (d, J ) 6.4 Hz, 1H), 1.32 (m, 6H), 1.41 (d, J ) 6.4 Hz, 3H), 1.51 (m, 6H), 2.44 (m, 1H), 2.45 (s, 3H), 2.58 (dd, J ) 16, 2.6 Hz, 1H), 2.71 (dd, J ) 16, 11 Hz, 1H), 3.62 (s, 3H), 3.63 (m, 1H), 3.72 (s, 3H), 6.34 (s, 1H). 13C NMR (75 MHz, CDCl ): δ 11.2, 13.7, 21.4, 23.3, 27.4, 29.2, 3 39.0, 41.4, 55.0, 55.2, 57.6, 61.8, 104.9, 119.7, 125.4, 139.3, 162.8, 163.5. HRMS: calcd for C26H47NSnO2 (M+ - CH3) 510.2394, found 510.2394. (1R*,3S*)-6,8-Dimethoxy-1,3-dimethyl-7-tributylstannanyl1,2,3,4-tetrahydroisoquinoline ((25). NaBH4 (78 mg) was added to a solution of the dihydroisoquinoline 5 (179 mg, 0.353 mmol) in MeOH (35 mL). The reaction was stirred for 30 min at room temperature, following which the solvent was removed under

Total Synthesis of Ancistrocladidine reduced pressure. The residue was dissolved in CH2Cl2 and filtered through a plug of Celite. Removal of the solvent under reduced pressure gave the title compound as a colorless oil (173 mg, 96%). 1H NMR (500 MHz, CDCl ): δ 0.87 (m, 9H), 1.04 (m, 6H), 1.21 3 (d, J ) 6.4 Hz, 3H), 1.30 (m, 6H), 1.48 (d, J ) 5.9 Hz, 3H), 1.50 (m, 6H), 2.48 (dd, J ) 16, 11 Hz, 1H), 2.69 (dd, J ) 16, 2.4 Hz, 1H), 2.91 (m, 1H), 3.57 (s, 3H), 3.70 (s, 3H), 4.25 (q, J ) 6.4 Hz, 1H), 6.32 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 11.2, 13.7, 22.4, 22.6, 27.3, 29.2, 39.8, 48.3, 50.1, 55.0, 60.7, 105.8, 120.2, 125.3, 139.6, 162.8, 164.2. HRMS: calcd for C17H45NO2Sn (M+ - Bu) 454.1768, found 454.1768. (1R*,3S*)-6,8-Dimethoxy-1,3-dimethyl-7-tributylstannanyl3,4-dihydro-1H-isoquinoline-2-carboxylic Acid Methyl Ester ((23). NEt3 (190 µL, 1.36 mmol) was added to a solution of the amine 25 (178 mg, 0.339 mmol) in dry CH2Cl2 at 0 °C. Methyl chloroformate (53 µL, 0.678 mmol) was added slowly added, and the reaction was allowed to warm to room temperature overnight. The resulting solution was diluted with CH2Cl2 and washed with water. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with 15% EtOAc/petroleum ether, to give the title compound as a colorless oil (148 mg, 77%). 1H NMR (500 MHz, CDCl3): δ 0.87 (m, 9H), 1.08 (m, 6H), 1.31 (m, 6H), 1.38 (d, J ) 6.4 Hz, 3H), 1.44 (d, J ) 7.3 Hz, 3H), 1.50 (m, 6H), 2.88 (dd, J ) 16, 8.8 Hz, 1H), 2.96 (dd, J ) 16, 6.8 Hz, 1H), 3.67 (s, 3H), 3.71 (s, 3H), 3.72 (s, 3H), 4.16 (br m, 1H), 5.54 (br m, 1H), 6.41 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 11.1, 13.5, 22.0 (br), 24.0(br), 27.3, 29.2, 35.6, 46.5, 47.3, 52.3, 55.1, 62.6, 105.4, 120.0, 125.0 (br), 137.0, 156.1 (br), 162.2, 163.5. IR (KBr): 1699 cm-1. HRMS: calcd for C27H47NO4Sn (M+ - Bu) 512.1823, found 512.1823. 2-(4-Iodo-3,5-dimethoxy-phenyl)-(1,3)-dioxolane (26). A solution of the aldehyde 8 (3.42 g, 11.7 mmol), 1,2-ethanediol (0.98 mL, 17.6 mmol), and p-toluenesulfonic acid (40 mg, 0.21 mmol) in benzene (80 mL) was heated at reflux under Dean-Stark conditions for 20 h. After this time Et2O (100 mL) and saturated aqueous NaHCO3 solution were added. The organic extract was washed with water, and the solvent was removed under reduced pressure to give the title compound as a white solid (3.89 g, 99%). Mp: 82-83 °C. 1H NMR (300 MHz, CDCl3): δ 3.91 (s, 3H), 4.00-4.17 (m, 4H), 5.80 (s, 1H), 6.64 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 56.6, 65.3, 78.2, 102.0, 103.1, 140.3, 159.4. HRMS: calcd for C11H13IO4 (M+) 335.9857, found 335.9859. Tributyl-(4-(1,3)-dioxolan-2-yl-2,6-dimethoxy-phenyl)stannane (27). A solution of t-BuLi in pentane (1.5 M, 10.2 mL, 15.2 mmol) was added dropwise via syringe to a stirred solution of the iodide 26 (2.05 g, 6.10 mmol) in dry THF (60 mL) at -95 °C. The resulting solution was stirred at -95 °C for 15 min, then ClSnBu3 (4.13 mL, 15.2 mmol) was slowly added, and the reaction was allowed to warm slowly to room temperature overnight. The resulting solution was poured into saturated aqueous NaHCO3 solution and extracted with EtOAc (×4). Evaporation of the solvent under reduced pressure gave the crude product, which was purified by flash chromatography on alumina, eluting with 5% ethyl acetate/ petroleum ether, to give the title compound as colorless oil (2.58 g, 85%). 1H NMR (500 MHz, CDCl3): δ ?0.87 (m, 9H), 1.01 (m, 6H), 1.30 (m, 6H), 1.48 (m, 6H), 3.75 (s, 3H), 4.00-4.17 (m, 4H), 5.80 (s, 1H), 6.62 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 11.2, 13.7, 27.3, 29.1, 55.1, 65.2, 100.9, 103.7, 117.8, 140.8, 165.1. HRMS: calcd for C23H40O4120Sn (M+ - Bu) 443.1245, found 443.1244. 4-[(1,3)-Dioxolan-2-yl]-2,6-dimethoxyphenyl Lead Triacetate (25). Pb(OAc)4 (95%, 3.02 g) was protected from light and stirred under high vacuum for 30 min. A solution of the stannane 27 (2.69 g, 5.39 mmol) and Hg(OAc)2 (86 mg, 0.27 mmol) in dry CH2Cl2 (55 mL) was added via cannula, and the reaction was stirred at room temperature for 24 h. After this time the solution was diluted with CH2Cl2 and rinsed through a plug of Celite. The solvent was removed under reduced pressure to give a residue, which was washed with petroleum ether (×4). The resulting solid was dried

under high vacuum to give the title compound as a light yellow solid (2.98 g, 93%), which was used immediately in the next reaction. 1H NMR (500 MHz, CDCl3): δ 2.08 (s, 9H), 3.90 (s, 6H), 4.03-4.10 (m, 4H), 5.81 (s, 1H), 6.82 (s, 2H). 3,5-Dimethoxy-4-(1-hydroxy-8-methoxy-3-methylnaphthalen2-yl)benzaldehyde (28). Dry pyridine (1.34 mL) was added dropwise to a solution of the aryllead compound 25 (2.98 g, 5.02 mmol) and the naphthol 3 (0.945 g, 5.02 mmol) in dry CH2Cl2 (50 mL). The reaction was stirred at room temperature, protected from light, for 24 h. After this time saturated aqueous NH4Cl solution was added, and the aqueous layer was extracted with EtOAc (×4). The combined organic extracts were washed with 1 M aqueous HCl solution. The solvent was removed under reduced pressure, and the residue was dissolved in THF (100 mL). A solution of 3% v/v aqueous H2SO4 solution (25 mL) was added, and the reaction was stirred vigorously for 1 h. The resulting solution was diluted with 1 M aqueous HCl solution and extracted with EtOAc (×4). Removal of the solvent under reduced pressure and purification by flash chromatography, eluting with 40% ethyl acetate/petroleum ether, gave the title compound as pale yellow solid (1.18 g, 67%). Mp: 196-197 °C. 1H NMR (500 MHz, CDCl3): δ 2.09 (s, 3H), 3.81 (s, 6H), 3.98 (s, 3H), 6.71 (d, J ) 7.8 Hz, 1H), 7.22 (s, 2H), 7.24 (s, 1H), 7.27 (m, 1H), 7.35 (d, J ) 8.3 Hz, 1H), 9.41 (s, 1H), 10.01 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.1, 55.8, 56.1, 103.1, 105.3, 113.2, 116.0, 118.5, 121.1, 122.0, 125.5, 136.1, 137.1, 137.2, 150.7, 156.0, 158.5, 191.9. IR (KBr): 1697, 3500 cm-1. HRMS: calcd for C21H20O5 (M+) 352.1311, found 352.1311. (E)-3-(3,5-Dimethoxy-4-(8-methoxy-1-methoxymethoxy-3-methylnaphthalen-2-yl)-phenyl)prop-2-en-1-ol (30). (a) A solution of the naphthol 28 (1.18 g, 3.34 mmol) in dry THF (45 mL) was added to a suspension of prewashed NaH (0.160 g, 6.68 mmol) in dry THF (10 mL). The reaction was stirred for 1 h at room temperature, resulting in a turbid red solution. MOM-Cl (1.27 mL, 16.7 mmol) was added dropwise, and the reaction was stirred at room temperature overnight. The reaction was poured into saturated aqueous NaHCO3 solution and extracted with EtOAc (×4). The solvent was removed under reduced pressure and the residue purified by flash chromatography, eluting with 50% EtOAc/ petroleum ether, to give 3,5-dimethoxy-4-(8-methoxy-1-methoxymethoxy-3-methylnaphthalen-2-yl)benzaldehyde as a white solid (1.08 g, 81%). Mp: 177-178 °C. 1H NMR (500 MHz, CDCl3): δ 2.09 (s, 3H), 2.80 (s, 3H), 3.79 (s, 6H), 3.95 (s, 3H), 4.86 (s, 2H), 6.80 (d, J ) 6.8 Hz, 1H), 7.19 (s, 2H), 7.34 (dd, J ) 8.3, 7.8 Hz, 1H), 7.38 (dd, J ) 8.3, 1.5 Hz), 1H), 7.52 (s, 1H), 10.01 (s, 1H). 13C NMR (75 MHz, CDCl ): δ 20.0, 55.9, 56.0, 56.1, 100.3, 104.8, 3 104.9, 118.6, 120.4, 122.9, 124.3, 126.0, 126.1, 136.1, 136.9, 137.1, 149.7, 155.8, 158.9. IR (KBr): 1693 cm-1. HRMS: calcd for C23H24O6 (M+) 396.1573, found 396.1573. (b) Triethyl phosphonoacetate (592 µL, 2.98 mmol) was added to a suspension of prewashed NaH (78 mg, 3.25 mmol) in dry benzene (8 mL) at 0 °C. The reaction was stirred for 15 min, and then a solution of the aldehyde (1.08 g, 2.71 mmol) in dry benzene (15 mL) was slowly added. The reaction was stirred for 1 h at 0 °C, warmed to room temperature, and stirred for a further 30 min, following which H2O was added. The aqueous layer was extracted with EtOAc (×4) and the combined organic extracts were washed with H2O (×2). Removal of the solvent under reduced pressure gave (E)-3-(3,5-dimethoxy-4-(8-methoxy-1-methoxymethoxy-3methylnaphthalen-2-yl)-phenyl)acrylic acid ethyl ester as a white solid (1.26 g, 100%). Mp: 181-182 °C. 1H NMR (500 MHz, CDCl3): δ 1.37 (t, J ) 7.1 Hz, 3H), 2.12(s, 3H), 2.84 (s, 3H), 3.74 (s, 6H), 3.94 (s, 3H), 4.30 (q, J ) 7.1 Hz, 2H), 4.86 (s, 2H), 6.50 (d, J ) 16 Hz, 1H), 6.78 (d, J ) 7.3 Hz, 1H), 6.83 (s, 2H), 7.32 (dd, J ) 8.3, 7.3 Hz, 1H), 7.35 (d, J ) 7.3 Hz, 1H), 7.51 (s, 1H), 7.73 (d, J ) 16 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.1, 20.0, 55.6, 55.7, 55.9, 60.3, 100.0, 103.3, 104.7, 117.8, 118.3, 118.6, 120.3, 124.0, 125.7, 126.4, 134.9, 136.5, 136.7, 144.8, 149.6, 155.6, 158.4, 166.7. IR (KBr): 1709 cm-1. HRMS: calcd for C27H30O7 (M+) 466.1992, found 466.1992. J. Org. Chem, Vol. 71, No. 19, 2006 7361

Bungard and Morris (c) Neat DIBAL-H (1.00 mL, 5.61 mmol) was added dropwise to solution of the ester (1.05 g, 2.24 mmol) in dry toluene (25 mL) at -78 °C. The reaction was stirred for 15 min at this temperature. After this time EtOAc (100 mL) was added, and the solution was allowed to warm to room temperature. Saturated aqueous NaHCO3 solution was added, and the solution swas tirred vigorously for 5 min, followed by filtration and separation of the layers. The aqueous layer was further extracted with EtOAc (×3), and the organic extracts combined. Removal of the solvent under reduced pressure and purification by flash chromatography, eluting with 60% EtOAc/ petroleum ether, gave the title compound 30 as a white solid (844 mg, 89%). Mp: 154-155 °C. 1H NMR (500 MHz, CDCl3): δ 2.11 (s, 3H), 2.87 (s, 3H), 3.72 (s, 6H), 3.94 (s, 3H), 4.36 (d, J ) 4.9 Hz, 2H), 4.84 (s, 2H), 6.42 (m, 1H), 6.65 (d, J ) 16 Hz, 1H), 6.69 (s, 2H), 6.77 (d, J ) 6.8 Hz, 1H), 7.31 (m, 1H), 7.36 (d, J ) 7.3 Hz, 1H), 7.50 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.1, 55.6, 55.7, 56.1, 63.1, 99.8, 101.9, 104.6, 115.2, 118.7, 120.3, 124.0, 125.6, 127.0, 128.5, 130.9, 136.6, 136.9, 137.5, 149.4, 155.6, 158.1. IR (KBr): 3500 cm-1. HRMS: calcd for C25H28O6 (M+) 424.1886, found 424.1886. (+)-(2S,3R)-{3-(3,5-Dimethoxy-4-(8-methoxy-1-methoxymethoxy-3-methyl-naphthalen-2-yl)-phenyl)-2,3-oxiranyl}methanol (31). Ti(OiPr)4 (20 µL, 0.068 mmol) was added to a solution of diisopropyl-D-tartrate (19 mg, 0.081 mmol) and powdered 4 Å molecular sieves (40 mg) in dry CH2Cl2 (5 mL) at -20 °C. An anhydrous solution of TBHP in dry CH2Cl2 (6.1 M, 439 µL, 2.69 mmol) was added at a rate that maintained the internal temp at -20 °C. The reaction was stirred for 30 min at this temperature, following which a solution of the allylic alcohol 30 (568 mg, 1.34 mmol) in dry CH2Cl2 (6 mL), previously stirred over 4 Å sieves for 30 min, was added at a rate as to maintain the internal temperature between -15 and -20 °C. The reaction was stirred for 5 h at -20 °C, and then 10% aqueous NaOH solution, saturated with brine, was added, followed by Et2O (15 mL). The solution was warmed to room temperature, and then dry MgSO4 (2.6 g) and Celite (0.33 g) were added. The suspension was stirred for 15 min, diluted with CH2Cl2, and filtered through a pad of Celite, eluting with CH2Cl2. Removal of the solvent under reduced pressure and purification by flash chromatography, eluting with 60% EtOAc/ petroleum ether, gave the title compound as a white solid (474 mg, 80%, 90% de). Recrystallization from toluene/petroleum ether gave material (372 mg, 63%) of >95% de. [R]20D +13.8 (c 3.99, CHCl3). Mp: 174-175 °C. 1H NMR (500 MHz, CDCl3): δ 1.83 (m, 3H), 2.09 (s, 3H), 2.86 (s, 3H), 3.25 (m, 1H), 3.71 (s, 6H), 3.85 (m, 1H), 3.94 (s, 3H), 3.99 (d, J ) 2.0 Hz, 1H), 4.09 (m, 1H), 4.83 (s, 2H), 6.585 (s, 1H), 6.590 (s, 1H), 6.78 (d, J ) 7.3 Hz, 1H), 7.31 (m, 1H), 7.36 (d, J ) 7.3 Hz, 1H), 7.50 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.1, 55.7, 56.0, 56.1, 61.20, 61.25, 62.5, 99.8, 100.8, 104.7, 115.5, 118.7, 120.3, 124.1, 125.6, 126.8, 136.6, 136.8, 137.9, 149.4, 155.6, 158.2. IR (KBr): 3485 cm-1. HRMS: electrospray calcd for C25H28O7 (M+ + Cl) 475.1524, found 475.1524. (+)-(2S,3R)-Toluene-4-sulfonic Acid 3-(3,5-Dimethoxy-4-(8methoxy-1-methoxy-methoxy-3-methyl-naphthalen-2-yl)-phenyl)-2,3-oxiranylmethyl Ester (33). Dry NEt3 (433 µL, 3.12 mmol) was added dropwise to a solution of the epoxy alcohol 31 (275 mg, 0.623 mmol) and DMAP (76 mg, 0.623 mmol) in dry CH2Cl2 (6 mL) at 0 °C. A solution of TsCl (131 mg, 0.686 mmol) in dry CH2Cl2 (2 mL) was slowly added, and the reaction was stirred at 0 °C for 1 h. Saturated aqueous NaHCO3 solution was added, and the product was extracted with EtOAc (×4). The combined organic extracts were washed with saturated aqueous NaHCO3 solution. Removal of the solvent under reduced pressure gave the title compound as a fluffy white solid (307 mg, 83%). [R]20D +29.3 (c 2.39, CHCl3). Mp: 80-81 °C. 1H NMR (500 MHz, CDCl3): δ 2.07 (s, 3H), 2.47 (s, 3H), 2.84 (s, 3H), 3.29 (m, 1H), 3.685 and 3.687 (s, 3H), 3.84 (d, J ) 2.0 Hz, 2H), 3.94 (s, 3H), 4.16 (dd, J ) 11, 5.4 Hz, 1H), 4.39 (dd, J ) 11, 3.4 Hz, 1H), 4.82 (s, 2H), 6.51 (s, 1H), 6.53 (s, 1H), 6.77 (d, J ) 7.8 Hz, 1H), 7.31 (t, J ) 7362 J. Org. Chem., Vol. 71, No. 19, 2006

7.8 Hz, 1H), 7.36 (d, J ) 7.8 Hz), 7.38 (d, J ) 8.3 Hz, 2H), 7.49 (s, 1H), 7.85 (d, J ) 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 20.1, 21.5, 55.7, 56.1, 56.6, 58.6, 69.2, 99.9, 100.6, 101.0, 104.7, 116.0, 118.7, 120.3, 124.1, 125.7, 126.7, 127.8, 129.9, 132.4, 136.6, 136.7, 136.8, 145.1, 149.6, 155.7, 158.3, 158.4. HRMS: calcd for C32H35O9 (M+ + H) 595.2002, found 595.1981. (-)-(2R)-1-(3,5-Dimethoxy-4-(8-methoxy-1-methoxymethoxy3-methylnaphthalen-2-yl)-phenyl)-propan-2-ol (32). A solution of LiAlH4 (1.0 M, 1.55 mL, 1.55 mmol) in THF was added dropwise to a solution of the tosylate 33 (307 mg, 0.516 mmol) in dry Et2O (50 mL) at 0 °C. The reaction was stirred for 2 h at 0 °C, then 30 min at room temperature. The resulting solution was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. Removal of the solvent under reduced pressure and purification by flash chromatography, eluting with 80% EtOAc/petroleum ether, gave the title compound as a fluffy white solid (206 mg, 94%). [R]20D -14.0 (c 4.10, CHCl3). Mp: 94-95 °C. 1H NMR (500 MHz, CDCl3): δ 1.29 (d, J ) 6.4 Hz, 3H), 2.11 (s, 3H), 2.73 (dd, J ) 13, 8.3 Hz, 1H), 2.85 (dd, J ) 13, 4.9 Hz, 1H), 2.88 (s, 3H), 3.70 (s, 6H), 3.94 (s, 3H), 4.07 (m, 1H), 4.84 (s, 2H), 6.51 (s, 2H), 6.78 (d, J ) 7.3 Hz, 1H), 7.31 (m, 1H), 7.36 (d, J ) 7.8 Hz, 1H), 7.51 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.2, 22.6, 46.5, 55.8, 55.9, 56.1, 68.9, 99.9, 104.6, 104.7, 104.8, 113.9, 118.9, 120.4, 124.1, 125.6, 127.1, 136.7, 137.1, 139.5, 149.5, 155.8, 158.2, 158.3. IR (film): 3427 cm-1. HRMS: calcd for C25H30O6 (M+) 426.2042, found 426.2042. (+)-(1S)-2-(3,5-Dimethoxy-4-(8-methoxy-1-methoxymethoxy3-methylnaphthalen-2-yl)-phenyl)-1-methylethylamine (29). (a) DEAD (90 µL, 0.570 mmol) was added to a solution of the alcohol 32 (194 mg, 0.456 mmol), PPh3 (0.149 g, 0.570 mmol), and phthalimide (84 mg, 0.570 mmol) in dry THF (6 mL) at 0 °C. The reaction was protected from light and allowed to warm to room temperature overnight. Saturated aqueous NaHCO3 solution was added, and the product extracted with EtOAc (×4). The combined organic extracts were washed with saturated aqueous NaHCO3 solution. The solvent was removed under reduced pressure, and the residue was passed through a short column of alumina, eluting with 25% EtOAc/petroleum ether. Removal of the solvent under reduced pressure and purification of the residue by flash chromatography, eluting with 40% EtOAc/petroleum ether, gave (1S)-2{2-(3,5-dimethoxy-4-(8-methoxy-1-methoxymethoxy-3-methylnaphthalen-2-yl)-phenyl)-1-methylethyl}isoindole-1,3-dione as a white solid (207 mg, 82%). [R]20D +120 (c 3.05, CHCl3). Mp: 8285 °C. 1H NMR (500 MHz, CDCl3): δ 1.60 (d, J ) 5.9 Hz, 3H), 1.88 (s, 3H), 2.61 (s, 3H), 3.12 (dd, J ) 14, 5.9 Hz, 1H), 3.43 (dd, J ) 11, 14 Hz, 1H), 3.54 (s, 3H), 3.60 (s, 3H), 3.90 (s, 3H), 4.704.80 (overlapping m, 2H and 1H), 6.44 (s, 1H), 6.47 (s, 1H), 6.74 (d, J ) 7.3 Hz, 1H), 7.27 (dd, J ) 7.8, 7.3 Hz, 1H), 7.32 (d, J ) 7.8 Hz, 1H), 7.43 (s, 1H), 7.67 (m, 2H), 7.75 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 18.5, 19.8, 40.1, 48.2, 55.5, 55.6, 55.7, 55.8, 99.6, 104.0, 104.4, 104.5, 113.6, 118.6, 120.2, 122.7, 123.9, 125.4, 126.9, 131.6, 133.7, 136.5, 136.9, 139.2, 149.4, 155.6, 157.7, 157.8, 168.1. IR (KBr): 1709, 1770 cm-1. HRMS: calcd for C33H33O7 (M+) 555.2257, found 555.2257. (b) A 40% aqueous MeNH2 soution (8 mL) was added to a solution of the phthalimide (234 mg, 0.420 mmol) in abs EtOH (10 mL). The reaction was heated at reflux for 1 h, following which most of the EtOH was removed under reduced pressure. Saturated aqueous NaHCO3 solution was added, and the product was extracted with EtOAc (×4). Removal of the solvent under reduced pressure gave amine (29) as a white solid (179 mg, 100%). [R]20D +13.8 (c 3.58, CHCl3). Mp: 45-46 °C. 1H NMR (500 MHz, CDCl3): δ 1.18 (d, J ) 6.4 Hz, 3H), 2.11 (s, 3H), 2.60 (dd, J ) 13, 8.3 Hz, 1H), 2.78 (dd, J ) 13, 5.4 Hz, 1H), 2.88 (s, 3H), 3.26 (m, 1H), 3.70 (s, 6H), 3.94 (s, 3H), 4.84 (s, 2H), 6.49 (s, 1H), 6.50 (s, 1H), 6.77 (d, J ) 7.3 Hz, 1H), 7.30 (m, 1H), 7.36 (d, J ) 7.8 Hz, 1H), 7.50 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.1, 23.0, 46.8, 48.4, 55.6, 55.7, 56.0, 99.7, 104.4, 104.5, 104.6, 113.5, 118.8, 120.3, 124.0, 125.5, 127.1, 136.5, 137.0, 140.4, 149.4, 155.7, 157.9, 158.0.

Total Synthesis of Ancistrocladidine IR (KBr): 3416, 3551 cm-1. HRMS: electrospray calcd for C25H31NO5 (M+ - CH3OH) 393.1940, found 393.1940. (+)-(1S)-N-{2-(3,5-Dimethoxy-4-(8-methoxy-1-methoxymethoxy-3-methyl-naphthalen-2-yl)-phenyl)-1-methylethyl}acetamide (34). Dry NEt3 (129 µL, 0.924 mmol) was added to a solution of the amine 29 (179 mg, 0.420 mmol) in dry CH2Cl2 at 0 °C. Freshly distilled AcCl (36 µL, 0.504 mmol) was added dropwise, and the reaction was allowed to warm slowly to room temperature overnight. The resulting solution was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 solution. Removal of the solvent under reduced pressure gave the title compound as a white solid (191 mg, 97%). [R]20D +16.7 (c 1.10, CHCl3). Mp: 200-202 °C. 1H NMR (500 MHz, CDCl3): δ1.15(d, J ) 6.8 Hz, 3H), 1.96 (s, 3H), 2.09 (s, 3H), 2.68 (dd, J ) 14, 7.8 Hz, 1H), 2.87 (s, 3H), 2.94 (dd, J ) 13, 5.4 Hz, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 3.94 (s, 3H), 4.30 (m, 1H), 4.84 (m, 2H), 5.35 (d, J ) 7.8 Hz, 1H), 6.46 (s, 1H) and 6.49 (s, 1H), 6.77 (d, J ) 6.8 Hz, 1H), 7.31 (m, 1H), 7.36 (d, J ) 7.3 Hz, 1H), 7.50 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 19.7, 20.1, 23.3, 43.2, 46.2, 55.7, 55.7, 56.1, 83.2, 99.8, 104.6, 104.6, 104.7, 113.7, 118.8, 120.3, 124.0, 125.5, 127.1, 136.6, 137.0, 139.2, 149.4, 155.7, 157.9, 158.0, 169.2. IR (KBr): 1568, 1636, 3061, 3242, 3416 cm-1. HRMS: calcd for C27H33NO6 (M+) 467.2308, found 467.2308. (-)-M-(3S)-2-(6,8-Dimethoxy-1,3-dimethyl-3,4-dihydroisoquinolin-7-yl)-8-methoxy-3-methyl-naphthalen-1-ol (1a) and (+)P-atropisomer (35). 2,4,6-Collidine (58 µL, 0.437 mmol) was added to a solution of the amide 34 (186 mg, 0.397 mmol) in dry CH3CN (2 mL). Freshly distilled POCl3 (41 µL, 0.437 mmol) was added, and the reaction was heated at reflux for 4 h. The resulting solution was cooled to room temperature, poured into saturated aqueous NaHCO3 solution, and extracted with EtOAc (×4). Removal of the solvent under reduced pressure and purification by flash chromatography on alumina, eluting with 50% EtOAc/ petroleum ether, gave the title compound as a 1:1 mixture of diastereoisomers (119 mg, 74%). The mixture was crystallized from toluene/petroleum ether. Concentration of the mother liquor and repeated crystallization gave a further crop of crystals. The combined crops of crystals from above were recrystallized from toluene/petroleum ether to give ancistrocladidine (1a) as a single diastereoisomer as determined by 1H NMR spectroscopy. [R]20D

-136 (c 1.84, CHCl3). Mp: 253-254 °C dec (lit.9a 245-247 °C dec; lit.9b 255-258 °C dec). 1H NMR (500 MHz, CDCl3): δ 1.42 (d, J ) 6.8 Hz, 3H), 2.16 (s, 3H), 2.45 (dd, J ) 15, 13 Hz, 1H), 2.48 (d, J ) 2.0 Hz, 3H), 2.68 (dd, J ) 15, 4.4 Hz, 1H), 3.37 (s, 3H), 3.43 (m, 1H), 3.75 (s, 3H), 4.01 (s, 3H), 6.63 (s, 1H), 6.72 (d, J ) 7.3 Hz, 1H), 7.25 (s, 1H), 7.28 (dd, J ) 8.3, 7.3 Hz, 1H), 7.36 (d, J ) 8.3 Hz, 1H), 9.61 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 20.5, 22.0, 26.9, 35.2, 51.5, 55.8, 56.0, 60.9, 103.1, 105.9, 113.3, 116.9, 117.1, 118.7, 118.8, 121.1, 125.6, 136.2, 137.8, 141.3, 151.3, 156.1, 157.7, 159.2, 163.1. IR (KBr): 3361 cm-1. HRMS: calcd for C25H27NO4 (M+) 405.1940, found 405.1940. Concentration of the mother liquor gave atropisomer 35 as a colorless gum shown to be 90% diastereomerically pure by 1H NMR spectroscopy. [R]20D +40.4 (c 0.292, CHCl3). 1H NMR (500 MHz, CDCl3): δ 1.44 (d, J ) 6.8 Hz, 3H), 2.19 (s, 3H), 2.43 (dd, J ) 15, 14 Hz, 1H), 2.47 (d, J ) 2.0 Hz, 3H), 2.67 (dd, J ) 16, 4.4 Hz, 1H), 3.41 (s, 3H), 3.41 (m, 1H), 3.76 (s, 3H), 4.01 (s, 3H), 6.64 (s, 1H), 6.73 (d, J ) 7.3 Hz, 1H), 7.27 (s, 1H), 7.29 (dd, J ) 8.3, 7.3 Hz, 1H), 7.37 (d, J ) 8.3 Hz, 1H), 9.59 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 20.6, 22.4, 26.6, 35.3, 51.5, 55.9, 56.0, 61.2, 103.1, 105.9, 113.3, 117.0, 117.3, 118.8, 118.9, 121.3, 125.6, 136.2, 138.0, 141.5, 151.1, 156.1, 157.7, 159.3, 163.2. IR (film): 3381 cm-1. HRMS: calcd for C25H27NO4 (M+) 405.1940, found 405.1940.

Acknowledgment. We thank the University of Canterbury and the University of Adelaide for financial assistance and Mr. Bruce Clark for mass spectrometry experiments. J.C.M. thanks the ARC Centre of Excellence for Free Radical Chemistry and Biotechnology for support for a period of study leave at the RSC, The Australian National University. Supporting Information Available: Characterization data for natural ancistrocladidine, synthetic ancistrocladidine, and atropisomer 35. Experimental details on the determination of diastereomeric excess. Copies of 1H and 13C NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO0611364

J. Org. Chem, Vol. 71, No. 19, 2006 7363